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1.
Dev Sci ; 26(1): e13249, 2023 01.
Article in English | MEDLINE | ID: mdl-35175668

ABSTRACT

The drive to move to music is evident across a variety of contexts, from the simple urge to tap our toe to a song on the radio, to massive crowds dancing in time at a rock concert. Though seemingly effortless, beat synchronization is difficult to master and children are often poor beat synchronizers. Nevertheless, auditory-motor integration is fundamental for many daily processes, such as speech. A topic that has been relatively understudied concerns how stimulus properties affect young children's movement in responses to auditory stimuli. In the present study, we examined how musical groove (adult-rated desire to move) affected 3.0- to 6.9-year-old children's free dancing in the comfort of their home (n = 78). In the high groove conditions, children danced more and with more energy compared to the low groove conditions. Moreover, in the high groove condition, children's movement tempos corresponded better with the tempos of the music. Results point to early childhood sensitivity to the musical features that motivate adults to move to music. High groove music may therefore prove especially effective at facilitating early auditory-motor integration. A video abstract of this article can be viewed at https://youtu.be/vli0-6N12Ts.


Subject(s)
Auditory Perception , Music , Adult , Child , Humans , Child, Preschool , Auditory Perception/physiology , Movement/physiology , Speech
2.
Heredity (Edinb) ; 129(4): 225-232, 2022 10.
Article in English | MEDLINE | ID: mdl-35764697

ABSTRACT

Mitochondria are organelles that produce cellular energy in the form of ATP through oxidative phosphorylation, and this primary function is conserved among many taxa. Locomotion is a trait that is highly reliant on metabolic function and expected to be greatly affected by disruptions to mitochondrial performance. To this end, we aimed to examine how activity and sleep vary between Drosophila melanogaster strains with different geographic origins, how these patterns are affected by mitochondrial DNA (mtDNA) variation, and how breaking up co-evolved mito-nuclear gene combinations affect the studied activity traits. Our results demonstrate that Drosophila strains from different locations differ in sleep and activity, and that females are generally more active than males. By comparing activity and sleep of mtDNA variants introgressed onto a common nuclear background in cytoplasmic hybrid (cybrid) strains, we were able to quantify the among-line variance attributable to mitochondrial DNA, and we establish that mtDNA variation affects both activity and sleep, in a sex-specific manner. Altogether our study highlights the important role that mitochondrial genome variation plays on organismal physiology and behaviour.


Subject(s)
DNA, Mitochondrial , Drosophila melanogaster , Adenosine Triphosphate/metabolism , Animals , DNA, Mitochondrial/genetics , Drosophila/genetics , Drosophila melanogaster/genetics , Female , Locomotion/genetics , Male , Mitochondria/genetics , Sleep/genetics
3.
Neurobiol Learn Mem ; 185: 107507, 2021 11.
Article in English | MEDLINE | ID: mdl-34474155

ABSTRACT

Our memory for time is a fundamental ability that we use to judge the duration of events, put our experiences into a temporal context, and decide when to initiate actions. The medial entorhinal cortex (MEC), with its direct projections to the hippocampus, has been proposed to be the key source of temporal information for hippocampal time cells. However, the behavioral relevance of such temporal firing patterns remains unclear, as most of the paradigms used for the study of temporal processing and time cells are either spatial tasks or tasks for which MEC function is not required. In this study, we asked whether the MEC is necessary for rats to perform a time duration discrimination task (TDD), in which rats were trained to discriminate between 10-s and 20-s delay intervals. After reaching a 90% performance criterion, the rats were assigned to receive an excitotoxic MEC-lesion or sham-lesion surgery. We found that after recovering from surgery, rats with MEC lesions were impaired on the TDD task in comparison to rats with sham lesions, failing to return to criterion performance. Their impairment, however, was specific to the longer, 20-s delay trials. These results indicate that time processing is dependent on MEC neural computations only for delays that exceed 10 s, perhaps because long-term memory resources are needed to keep track of longer time intervals.


Subject(s)
Entorhinal Cortex/physiology , Memory, Episodic , Time Perception/physiology , Animals , Conditioning, Operant/physiology , Discrimination Learning , Entorhinal Cortex/injuries , Male , Memory Disorders/physiopathology , Rats , Rats, Long-Evans
4.
J Invertebr Pathol ; 184: 107595, 2021 09.
Article in English | MEDLINE | ID: mdl-33878331

ABSTRACT

Invasive crayfish and the introduction of non-native diseases pose a significant risk for the conservation of endangered, white-clawed crayfish (Austropotamobius pallipes). Continued pollution of waterways is also of concern for native species and may be linked with crayfish disease dynamics. We explore whether crayfish species or environmental quality are predictors of infection presence and prevalence in native A. pallipes and invasive signal crayfish (Pacifastacus leniusculus). We use a seven-year dataset of histology records, and a field survey comparing the presence and prevalence of infectious agents in three isolated A. pallipes populations; three isolated P. leniusculus populations, and three populations where the two species had overlapped in the past. We note a lower diversity of parasites (Simpson's Index) in P. leniusculus ('Pacifastacus leniusculus Bacilliform Virus' - PlBV) (n = 1 parasite) relative to native A. pallipes (n = 4 parasites), which host Thelohania contejeani, 'Austropotamobius pallipes bacilliform virus' (ApBV), Psorospermium haeckeli and Branchiobdella astaci, at the sites studied. The infectious group present in both species was an intranuclear bacilliform virus of the hepatopancreas. The prevalence of A. astaci in A. pallipes populations was higher in more polluted water bodies, which may reflect an effect of water quality, or may be due to increased chance of transmission from nearby P. leniusculus, a species commonly found in poor quality habitats.


Subject(s)
Astacoidea/microbiology , Astacoidea/parasitology , Introduced Species , Animals , Astacoidea/virology , United Kingdom
5.
J Neurosci Res ; 98(9): 1780-1799, 2020 09.
Article in English | MEDLINE | ID: mdl-31562661

ABSTRACT

The ability to perceive and interpret environmental sound accurately is conserved across many species and is fundamental for understanding communication via vocalizations. Auditory acuity and temporally controlled neuronal firing underpin this ability. Deterioration in neuronal firing precision likely contributes to poorer hearing performance, yet the role of neural processing by key nuclei in the central auditory pathways is not fully understood. Here, we record from the auditory thalamus (medial geniculate body [MGB]) of young and middle-aged, normally hearing male CBA/Ca mice. We report changes in temporal processing of auditory stimuli, with neurons recorded from ventral and medial MGB subdivisions of older animals more likely to synchronize to rapid temporally varying stimuli. MGB subdivisions also showed increased probability of neuronal firing and shorter response latencies to clicks in older animals. Histological investigation of neuronal extracellular specializations, perineuronal nets (PNNs) and axonal coats, in the MGB identified greater organization of PNNs around MGB neurons and the presence of axonal coats within older animals. This supports the observation that neural responses recorded from ventral and medial MGB of older mice were more likely to synchronize to temporally varying stimuli presented at faster repetition rates than those recorded from young adult animals. These changes are observed in animals with normal hearing thresholds, confirming that neural processing differs between the MGB subdivisions and such processing is associated with age-related changes to PNNs. Understanding these age-related changes and how they occur have important implications for the design of effective therapeutic interventions to improve speech intelligibility into later life.


Subject(s)
Aging/physiology , Auditory Perception/physiology , Geniculate Bodies/physiology , Acoustic Stimulation , Animals , Auditory Pathways/physiology , Geniculate Bodies/anatomy & histology , Hearing/physiology , Male , Mice , Mice, Inbred CBA , Neurons/physiology , Time Perception/physiology
6.
J Neurosci ; 36(6): 1977-95, 2016 Feb 10.
Article in English | MEDLINE | ID: mdl-26865621

ABSTRACT

High temporal acuity of auditory processing underlies perception of speech and other rapidly varying sounds. A common measure of auditory temporal acuity in humans is the threshold for detection of brief gaps in noise. Gap-detection deficits, observed in developmental disorders, are considered evidence for "sluggish" auditory processing. Here we show, in a mouse model of gap-detection deficits, that auditory brain sensitivity to brief gaps in noise can be impaired even without a general loss of central auditory temporal acuity. Extracellular recordings in three different subdivisions of the auditory thalamus in anesthetized mice revealed a stimulus-specific, subdivision-specific deficit in thalamic sensitivity to brief gaps in noise in experimental animals relative to controls. Neural responses to brief gaps in noise were reduced, but responses to other rapidly changing stimuli unaffected, in lemniscal and nonlemniscal (but not polysensory) subdivisions of the medial geniculate body. Through experiments and modeling, we demonstrate that the observed deficits in thalamic sensitivity to brief gaps in noise arise from reduced neural population activity following noise offsets, but not onsets. These results reveal dissociable sound-onset-sensitive and sound-offset-sensitive channels underlying auditory temporal processing, and suggest that gap-detection deficits can arise from specific impairment of the sound-offset-sensitive channel. SIGNIFICANCE STATEMENT: The experimental and modeling results reported here suggest a new hypothesis regarding the mechanisms of temporal processing in the auditory system. Using a mouse model of auditory temporal processing deficits, we demonstrate the existence of specific abnormalities in auditory thalamic activity following sound offsets, but not sound onsets. These results reveal dissociable sound-onset-sensitive and sound-offset-sensitive mechanisms underlying auditory processing of temporally varying sounds. Furthermore, the findings suggest that auditory temporal processing deficits, such as impairments in gap-in-noise detection, could arise from reduced brain sensitivity to sound offsets alone.


Subject(s)
Auditory Perception/physiology , Time Perception/physiology , Acoustic Stimulation , Adaptation, Psychological , Algorithms , Animals , Auditory Perception/genetics , Evoked Potentials, Auditory, Brain Stem/physiology , Excitatory Postsynaptic Potentials/physiology , Geniculate Bodies/physiology , Hearing/physiology , Male , Mice , Models, Neurological , Mutation/genetics , Noise , Thalamus/physiology
7.
Ann Bot ; 117(2): 341-7, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26658101

ABSTRACT

BACKGROUND AND AIMS: Most pollinators are generalists and therefore are likely to transfer heterospecific pollen among co-flowering plants. Most work on the impacts of heterospecific pollen deposition on plant fecundity has utilized hand-pollination experiments in greenhouse settings, and we continue to know very little about the reproductive effects of heterospecific pollen in field settings. METHODS: We explored how patterns of naturally deposited heterospecific pollen relate to the reproductive output of Delphinium barbeyi, a common subalpine perennial herb in the Rocky Mountains (USA). We assessed a wide range of naturally occurring heterospecific pollen proportions and pollen load sizes, and linked stigmatic pollen deposition directly to seed set in individual carpels in the field. KEY RESULTS: We found that heterospecific pollen deposition in D. barbeyi is common, but typically found at low levels across stigmas collected in our sites. Neither conspecific nor heterospecific pollen deposition was related to carpel abortion. By contrast, we saw a significant positive relationship between conspecific pollen amount and viable seed production, as well as a significant negative interaction between the effects of conspecific pollen and heterospecific pollen amount, whereby the effect of conspecific pollen on viable seed production became weaker with greater heterospecific deposition on stigmas. CONCLUSIONS: To our knowledge, this is the first demonstration of a relationship between heterospecific pollen and seed production in a field setting. In addition, it is the first report of an interaction between conspecific and heterospecific pollen quantities on seed production. These findings, taken with the results from other studies, suggest that greenhouse hand-pollination studies and field studies should be more tightly integrated in future work to better understand how heterospecific pollen transfer can be detrimental for plant reproduction.


Subject(s)
Delphinium/physiology , Pollen/physiology , Colorado , Flowers/physiology , Pollination , Reproduction/physiology , Seeds/physiology
8.
Proc Natl Acad Sci U S A ; 108(46): 18732-6, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-22065772

ABSTRACT

Batrachochytrium dendrobatidis (Bd) is a globally ubiquitous fungal infection that has emerged to become a primary driver of amphibian biodiversity loss. Despite widespread effort to understand the emergence of this panzootic, the origins of the infection, its patterns of global spread, and principle mode of evolution remain largely unknown. Using comparative population genomics, we discovered three deeply diverged lineages of Bd associated with amphibians. Two of these lineages were found in multiple continents and are associated with known introductions by the amphibian trade. We found that isolates belonging to one clade, the global panzootic lineage (BdGPL) have emerged across at least five continents during the 20th century and are associated with the onset of epizootics in North America, Central America, the Caribbean, Australia, and Europe. The two newly identified divergent lineages, Cape lineage (BdCAPE) and Swiss lineage (BdCH), were found to differ in morphological traits when compared against one another and BdGPL, and we show that BdGPL is hypervirulent. BdGPL uniquely bears the hallmarks of genomic recombination, manifested as extensive intergenomic phylogenetic conflict and patchily distributed heterozygosity. We postulate that contact between previously genetically isolated allopatric populations of Bd may have allowed recombination to occur, resulting in the generation, spread, and invasion of the hypervirulent BdGPL leading to contemporary disease-driven losses in amphibian biodiversity.


Subject(s)
Amphibians/microbiology , Chytridiomycota/genetics , Chytridiomycota/physiology , Virulence , Animals , Biodiversity , Cell Lineage , Genetic Variation , Genotype , Heterozygote , Homozygote , Models, Genetic , Phylogeny , Polymorphism, Single Nucleotide , Recombinant Proteins/metabolism , Recombination, Genetic
9.
Brain Behav Immun Health ; 35: 100700, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38107021

ABSTRACT

Attention-deficit/hyperactivity disorder (ADHD) is a complex behavioral disorder characterized by hyperactivity, impulsivity, inattention, and deficits in working memory and time perception. While animal models have advanced our neurobiological understanding of this condition, there are limited and inconsistent data on working and elapsed time memory function. Inflammatory signaling has been identified as a key factor in memory and cognitive impairments, but its role in ADHD remains unclear. Additionally, the disproportionate investigation of male subjects in ADHD research has contributed to a poor understanding of the disorder in females. This study sought to investigate the potential connections between memory, neuroimmunology, and ADHD in both male and female animals. Specifically, we utilized the spontaneously hypertensive rat (SHR), one of the most extensively studied animal models of ADHD. Compared to their control, the Wistar-Kyoto (WKY) rat, male SHR are reported to exhibit several behavioral phenotypes associated with ADHD, including hyperactivity, impulsivity, and poor sustained attention, along with impairments in learning and memory. As the hippocampus is a key brain region for learning and memory, we examined the behavior of male and female SHR and WKY rats in two hippocampal-dependent memory tasks. Our findings revealed that SHR have delay-dependent working memory deficits that were similar to, albeit less severe than, those seen in hippocampal-lesioned rats. We also observed impairments in elapsed time processing in female SHR, particularly in the discrimination of longer time durations. To investigate the impact of inflammatory signaling on memory in these rats, we analyzed the levels of several cytokines in the dorsal and ventral hippocampus of SHR and WKY. Although we found some sex and genotype differences, concentrations were generally similar between groups. Taken together, our results indicate that SHR exhibit deficits in spatial working memory and memory for elapsed time, as well as some differences in hippocampal cytokine concentrations. These findings contribute to a better understanding of the neurobiological basis of ADHD in both sexes and may inform future research aimed at developing effective treatments for the disorder. Nonetheless, the potential mediating role of neuroinflammation in the memory symptomatology of SHR requires further investigation.

10.
PLoS One ; 19(2): e0281408, 2024.
Article in English | MEDLINE | ID: mdl-38315706

ABSTRACT

Since 1997 Tanzania has undertaken a process to identify and declare a network of Nature Forest Reserves (NFRs) with high biodiversity values, from within its existing portfolio of national Forest Reserves, with 16 new NFRs declared since 2015. The current network of 22 gazetted NFRs covered 948,871 hectares in 2023. NFRs now cover a range of Tanzanian habitat types, including all main forest types-wet, seasonal, and dry-as well as wetlands and grasslands. NFRs contain at least 178 of Tanzania's 242 endemic vertebrate species, of which at least 50% are threatened with extinction, and 553 Tanzanian endemic plant taxa (species, subspecies, and varieties), of which at least 50% are threatened. NFRs also support 41 single-site endemic vertebrate species and 76 single-site endemic plant taxa. Time series analysis of management effectiveness tracking tool (METT) data shows that NFR management effectiveness is increasing, especially where donor funds have been available. Improved management and investment have resulted in measurable reductions of some critical threats in NFRs. Still, ongoing challenges remain to fully contain issues of illegal logging, charcoal production, firewood, pole-cutting, illegal hunting and snaring of birds and mammals, fire, wildlife trade, and the unpredictable impacts of climate change. Increased tourism, diversified revenue generation and investment schemes, involving communities in management, and stepping up control measures for remaining threats are all required to create a network of economically self-sustaining NFRs able to conserve critical biodiversity values.


Subject(s)
Conservation of Natural Resources , Forests , Animals , Tanzania , Conservation of Natural Resources/methods , Ecosystem , Biodiversity , Mammals
11.
Int J Cancer ; 130(2): 251-8, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-21387307

ABSTRACT

The use of siRNAs against specific molecular targets has potential for cancer therapy but has been thought to be limited by the need for formulation to improve cellular uptake. Lung adenocarcinoma cells are markedly suppressed in culture by siRNAs to the receptor ERBB3 or its downstream signaling partner AKT2. We now demonstrate that naked, unformulated siRNAs to ERBB3 or AKT2, administered i.v. as saline solutions, 2 µg/g five times per week for 3 weeks (total dose 30 µg/g), were effective suppressors of growth of A549 human lung adenocarcinoma cell xenografts in athymic mice, 12 mice per group, in four different experiments. ERBB3 and AKT2 siRNAs each inhibited growth by 70-90% on average, compared to saline-treated or untreated controls; a nonsilencing siRNA was without significant effect. Lesser but significant effects were noted with a total dose of 12 µg/g. With the higher dose, effects persisted for several weeks after the end of treatment. Expected reductions of ERBB3 and AKT2 mRNAs and proteins occurred and correlated with decrease in tumor volume. There were no significant changes in serum cytokines. These results show that naked siRNAs to ERBB3 or AKT2 may have potential for lung cancer therapy.


Subject(s)
Adenocarcinoma/therapy , Lung Neoplasms/therapy , Proto-Oncogene Proteins c-akt/genetics , RNA, Small Interfering/administration & dosage , Receptor, ErbB-3/genetics , Adenocarcinoma/enzymology , Adenocarcinoma/genetics , Adenocarcinoma of Lung , Animals , Cell Growth Processes/genetics , Cytokines/blood , Gene Silencing , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Mice , Mice, Nude , Proto-Oncogene Proteins c-akt/biosynthesis , RNA, Antisense/administration & dosage , RNA, Antisense/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Random Allocation , Receptor, ErbB-3/biosynthesis , Xenograft Model Antitumor Assays
12.
Cancer Causes Control ; 23(6): 983-90, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22527169

ABSTRACT

It is becoming increasingly evident that early-life events and exposures have important consequences for cancer development later in life. However, epidemiological studies of early-life factors and cancer development later in life have had significant methodological challenges such as the long latency period, the distinctiveness of each cancer, and large number of subjects that must be studied, all likely to increase costs. These traditional hurdles might be mitigated by leveraging several existing large-scale prospective studies in the United States (US) and globally, as well as birth databases and birth cohorts, in order to launch both association and mechanistic studies of early-life exposures and cancer development later in life. Dedicated research funding will be needed to advance this paradigm shift in cancer research, and it seems justified by its potential to produce transformative understanding of how cancer develops over the life-course. This in turn has the potential to transform cancer prevention strategies through interventions in early-life rather than later in life, as is the current practice, where it is perhaps less effective.


Subject(s)
Environmental Exposure/statistics & numerical data , Neoplasms/epidemiology , Age Factors , Animals , Environmental Exposure/adverse effects , Environmental Exposure/analysis , Epidemiologic Studies , Humans , Life Change Events , Neoplasms/etiology , Prospective Studies , Risk Factors
13.
Bioorg Med Chem ; 20(9): 3094-9, 2012 May 01.
Article in English | MEDLINE | ID: mdl-22480849

ABSTRACT

JS-K, a diazeniumdiolate-based nitric oxide (NO)-releasing prodrug, is currently in late pre-clinical development as an anti-cancer drug candidate. This prodrug was designed to be activated by glutathione (GSH) to release NO. To increase the potency of JS-K, we are investigating the effect of slowing the reaction of the prodrugs with GSH. Herein, we report the effect of replacement of nitro group(s) by other electron-withdrawing group(s) in JS-K and its homo-piperazine analogues on GSH activation and the drugs' biological activity. We show that nitro-to-cyano substitution increases the half-life of the prodrug in the presence of GSH without compromising the compound's in vivo antitumor activity.


Subject(s)
Antineoplastic Agents/chemistry , Azo Compounds/chemistry , Glutathione/metabolism , Prodrugs/chemistry , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Azo Compounds/pharmacology , Drug Stability , Half-Life , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Kinetics , Mice , Neoplasms/drug therapy , Nitric Oxide/metabolism , Prodrugs/pharmacology , Signal Transduction/drug effects
14.
JCI Insight ; 7(3)2022 02 08.
Article in English | MEDLINE | ID: mdl-35132964

ABSTRACT

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.


Subject(s)
Blindness/congenital , Disease Management , Evoked Potentials, Auditory, Brain Stem/physiology , Forecasting , Genetic Diseases, X-Linked/physiopathology , Hearing Loss, Sensorineural/physiopathology , Hearing/physiology , Nervous System Diseases/physiopathology , Retinal Degeneration/physiopathology , Spasms, Infantile/physiopathology , Adolescent , Adult , Animals , Blindness/complications , Blindness/physiopathology , Blindness/therapy , Child , Child, Preschool , Disease Models, Animal , Female , Follow-Up Studies , Genetic Diseases, X-Linked/complications , Genetic Diseases, X-Linked/therapy , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/etiology , Humans , Male , Mice , Mice, Mutant Strains , Nervous System Diseases/complications , Nervous System Diseases/therapy , Retinal Degeneration/complications , Retinal Degeneration/therapy , Spasms, Infantile/complications , Spasms, Infantile/therapy , Young Adult
15.
J Pharmacol Exp Ther ; 336(2): 313-20, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20962031

ABSTRACT

Non-small-cell lung cancer is among the most common and deadly forms of human malignancies. Early detection is unusual, and there are no curative therapies in most cases. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Here, we show that O(2)-(2,4-dinitrophenyl)-1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) is a potent cytotoxic agent against a subset of human non-small-cell lung cancer cell lines both in vitro and as xenografts in mice. JS-K treatment led to 75% reduction in the growth of H1703 lung adenocarcinoma cells in vivo. Differences in sensitivity to JS-K in different lung cancer cell lines seem to be related to their endogenous levels of reactive oxygen species (ROS)/reactive nitrogen species (RNS). Other related factors, levels of peroxiredoxin 1 (PRX1) and 8-oxo-deoxyguanosine glycosylase (OGG1), also correlated with drug sensitivity. Treatment of the lung adenocarcinoma cells with JS-K resulted in oxidative/nitrosative stress in cells with high basal levels of ROS/RNS, which, combined with the arylating properties of the compound, was reflected in glutathione depletion and alteration in cellular redox potential, mitochondrial membrane permeabilization, and cytochrome c release. Inactivation of manganese superoxide dismutase by nitration was associated with increased superoxide and significant DNA damage. Apoptosis followed these events. Taken together, the data suggest that diazeniumdiolate-based NO-releasing prodrugs may have application as a personalized therapy for lung cancers characterized by high levels of ROS/RNS. PRX1 and OGG1 proteins, which can be easily measured, could function as biomarkers for identifying tumors sensitive to the therapy.


Subject(s)
Antineoplastic Agents/pharmacology , Azo Compounds/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Piperazines/pharmacology , Reactive Oxygen Species/metabolism , Animals , Apoptosis/drug effects , Azo Compounds/therapeutic use , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , DNA Damage , Female , Glutathione/metabolism , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mitochondria/metabolism , Piperazines/therapeutic use , Reactive Nitrogen Species/metabolism , Xenograft Model Antitumor Assays
16.
Health Info Libr J ; 28(1): 3-22, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21314890

ABSTRACT

BACKGROUND: Previous systematic reviews have indicated limited evidence and poor quality evaluations of clinical librarian (CL) services. Rigorous evaluations should demonstrate the value of CL services, but guidance is needed before this can be achieved. OBJECTIVES: To undertake a systematic review which examines models of CL services, quality, methods and perspectives of clinical librarian service evaluations. METHODS: Systematic review methodology and synthesis of evidence, undertaken collaboratively by a group of 8 librarians to develop research and critical appraisal skills. RESULTS: There are four clear models of clinical library service provision. Clinical librarians are effective in saving health professionals time, providing relevant, useful information and high quality services. Clinical librarians have a positive effect on clinical decision making by contributing to better informed decisions, diagnosis and choice of drug or therapy. The quality of CL studies is improving, but more work is needed on reducing bias and providing evidence of specific impacts on patient care. The Critical Incident Technique as part of a mixed method approach appears to offer a useful approach to demonstrating impact. CONCLUSIONS: This systematic review provides practical guidance regarding the evaluation of CL services. It also provides updated evidence regarding the effectiveness and impact of CL services. The approach used was successful in developing research and critical appraisal skills in a group of librarians.


Subject(s)
Libraries, Medical/organization & administration , Library Services/organization & administration , Professional Competence , Professional Role , Quality of Health Care , Cooperative Behavior , Humans , Information Dissemination , Interprofessional Relations , Librarians , Models, Organizational , Total Quality Management
17.
J Neurosci ; 29(22): 7359-63, 2009 Jun 03.
Article in English | MEDLINE | ID: mdl-19494157

ABSTRACT

Neurons in the primary auditory cortex respond less strongly to a commonly occurring "standard" tone than to the same tone when it is rare or "deviant." This phenomenon, called "stimulus-specific adaptation" (SSA), has been proposed as a possible single-neuron correlate of the mismatch negativity, a cortical evoked potential associated with stimulus novelty. Previous studies in cat did not observe SSA in single neurons in the auditory thalamus. However, these reports did not differentiate between the auditory thalamic subdivisions and did not examine the effects of changing the stimulus presentation rate. To explore the possibility of thalamic SSA more completely, we recorded extracellularly from 30 single units and 22 multiunit clusters in the ventral, medial, and dorsal subdivisions of the mouse medial geniculate body (MGB), while presenting the anesthetized animals with sequences of standard and deviant tones at interstimulus intervals of 400, 500 and 800 ms. We found SSA in the auditory thalamus at all three stimulus presentation rates, primarily in the medial subdivision but to a lesser degree also in the ventral MGB. Thalamic SSA was evident from the earliest onset of tone-evoked activity, although the latencies of responses to standard and deviant tones were not significantly different. Together with related findings of SSA in neurons of the "belt" regions of the inferior colliculus, these results demonstrate that SSA is present at subcortical levels, primarily in but not restricted to the nonlemniscal auditory pathway.


Subject(s)
Adaptation, Physiological/physiology , Geniculate Bodies/cytology , Sensory Receptor Cells/physiology , Acoustic Stimulation/methods , Animals , Evoked Potentials, Auditory/physiology , Geniculate Bodies/physiology , Male , Mice , Mice, Inbred CBA , Psychoacoustics , Sensory Receptor Cells/classification , Time Factors
18.
Sci Total Environ ; 704: 135242, 2020 Feb 20.
Article in English | MEDLINE | ID: mdl-31812404

ABSTRACT

Understanding and managing plastic pollution is an increasingly important environmental priority for policy makers, businesses and scientists. Awareness of the potential damage to the world's oceans has grown but there is less attention given to freshwater ecosystems. Yet, rivers are the dominant source of plastic pollution to the marine environment, as well as a potential sink, accumulating plastic from multiple sources. Actions to reduce the presence of macroplastics in rivers is fundamental to conserving both freshwater and marine environments, but there is limited understanding of potential pollution sources, vectors and storage. Importantly, there are only a handful of studies examining the typologies of freshwater macroplastic pollution, often using different categories and collection methods. This impedes setting priorities for scientific investigation and mitigation measures. The present study identifies the most prevalent macroplastic items in freshwater environments in Europe, with a focus on consumer plastic items, i.e. those that could potentially be reduced by targeted actions by the public, as well as industrial and government intervention. Our analysis addresses the differences between reported macroplastics in freshwater and marine environments as well as those estimated from litter rates. Our results identify a macroplastic "top ten", i.e. those dominant plastic typologies that require a more focused effort to reformulate their use and management, as well as setting a common baseline for a more consistent data gathering and reporting approach.

19.
PLoS One ; 15(8): e0236410, 2020.
Article in English | MEDLINE | ID: mdl-32797095

ABSTRACT

The use and management of single use plastics is a major area of concern for the public, regulatory and business worlds. Focusing on the most commonly occurring consumer plastic items present in European freshwater environments, we identified and evaluated consumer-based actions with respect to their direct or indirect potential to reduce macroplastic pollution in freshwater environments. As the main end users of these items, concerned consumers are faced with a bewildering array of choices to reduce their plastics footprint, notably through recycling or using reusable items. Using a Multi-Criteria Decision Analysis approach, we explored the effectiveness of 27 plastic reduction actions with respect to their feasibility, economic impacts, environmental impacts, unintended social/environmental impacts, potential scale of change and evidence of impact. The top ranked consumer-based actions were identified as: using wooden or reusable cutlery; switching to reusable water bottles; using wooden or reusable stirrers; using plastic free cotton-buds; and using refill detergent/ shampoo bottles. We examined the feasibility of top-ranked actions using a SWOT analysis (Strengths, Weaknesses, Opportunities and Threats) to explore the complexities inherent in their implementation for consumers, businesses, and government to reduce the presence of plastic in the environment.


Subject(s)
Environmental Monitoring , Plastics/toxicity , Rivers/chemistry , Water Pollutants, Chemical/toxicity , Consumer Behavior , Decision Support Techniques , Environmental Pollution , Humans , Plastics/chemistry , Recycling , Waste Products/analysis , Water Pollutants, Chemical/chemistry
20.
Biochemistry ; 48(32): 7575-83, 2009 Aug 18.
Article in English | MEDLINE | ID: mdl-19583261

ABSTRACT

K-Ras4B belongs to the family of p21 Ras GTPases, which play an important role in cell proliferation, survival, and motility. The p21 Ras proteins, such as K-Ras4B, K-Ras4A, H-Ras, and N-Ras, share 85% sequence homology and activate very similar signaling pathways. Only the C-terminal hypervariable regions differ significantly. A growing body of literature demonstrates that each Ras isoform possesses unique functions in normal physiological processes as well as in pathogenesis. One of the central questions in the field of Ras biology is how these very similar proteins achieve such remarkable specificity in protein-protein interactions that regulate signal transduction pathways. Here we explore specific binding of K-Ras4B to calmodulin. Using NMR techniques and isothermal titration calorimetry, we demonstrate that the hypervariable region of K-Ras4B contributes in a major way to the interaction with calmodulin, while the catalytic domain of K-Ras4B provides a way to control the interaction by nucleotide binding. The hypervariable region of K-Ras4B binds specifically to the C-terminal domain of Ca(2+)-loaded calmodulin with micromolar affinity, while the GTP-gamma-S-loaded catalytic domain of K-Ras4B may interact with the N-terminal domain of calmodulin.


Subject(s)
Calmodulin/chemistry , Calmodulin/metabolism , Isoenzymes/chemistry , Isoenzymes/metabolism , Protein Conformation , Proto-Oncogene Proteins p21(ras)/chemistry , Proto-Oncogene Proteins p21(ras)/metabolism , Binding Sites , Calmodulin/genetics , Humans , Isoenzymes/genetics , Models, Molecular , Nuclear Magnetic Resonance, Biomolecular , Protein Binding , Proto-Oncogene Proteins p21(ras)/genetics , Signal Transduction/physiology
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